Merck Sharp & Dohme Limited

Section 4.3

New statement added:

·         tibolone increased the risk of breast cancer recurrence in a placebo controlled trial.

Section 5.1

Paragraph removed:

In vitro studies:

In vitro studies suggest that tibolone exerts tissue-selective effects, due to local metabolism and local effects on enzyme systems. The Δ⁴-isomer is mainly formed in endometrial tissue, and in the breast tibolone inhibits the sulfatase enzyme thereby reducing the levels of 3-OH-tibolone metabolites in this tissue. The clinical relevance of these studies is not known (see section 4.8).

Section 9

Date of renewal of the authorization

From 1996 to March 2009

Section 10

Date of revision of text

From February 2008 to March 2009

Section 3

Tablet description expanded

Section 4.1

Statements added:

 “more than one year after menopause”

“For all women the decision to prescribe tibolone should be based on an assessment of the individual patient’s overall risks and, particularly in the over 60s, should include consideration of the risk of stroke (see sections 4.4 and 4.8).”

Statement removed:

including vasomotor symptoms, depressed mood, decreased libido) in postmenopausal women.

Section 4.2

Statement added:

Statement removed:

“without interruption”     without chewing

“For the treatment of oestrogen deficiency symptoms and the prevention of osteoporosis”

“Any irregular/unscheduled vaginal bleeding, either on or off HRT, for which there is no obvious cause, should be investigated before starting Livial (see section 4.3)”

“Children

Not applicable.”

Statement combined:

“Women experiencing a natural menopause should commence treatment with Livial at least 12 months after their last natural bleed.

 Women experiencing a surgical menopause may commence treatment with Livial immediately”.

“If changing from a Sequential HRT preparation, treatment with Livial should start the day following completion of the prior regimen.

If changing from a Continuous-combined HRT preparation, treatment can start at any time.”

Missed pills

“A missed dose should be taken as soon as remembered, unless it is more than 12 hours overdue. In the latter case, the missed dose should be skipped and the next dose should be taken at the normal time.

Missing a dose may increase the likelihood of breakthrough bleeding and spotting.”

Section 4.3

Statement added/changed:

“Lactation”

“vaginal” changed to “genital”

Section 4.4

Statement added/changed:

HRT changed to Tibolone

“Stroke” added

New statement added under other conditions section:

“Treatment with Livial results in a marked dose-dependent decrease in HDL cholesterol (from -16.7% with a 1.25 mg dose to -21.8% for the 2.5 mg dose after 2 years). Total triglycerides and lipoprotein(a) levels were also reduced. The decrease in total cholesterol and VLDL-C levels was not dose-dependent. Levels of LDL-C were unchanged. The clinical implication of these findings is not yet known.”

Statement removed:

Hyperplasia

Endometrial  breast cancer and Stroke sections updated

Tibolone is removed from the Ovarian cancer section

Section 4.5

Statement added

“An in vivo study showed that simultaneous treatment of tibolone affects pharmacokinetics of the cytochrome P450 3A4 substrate midazolam to a moderate extent. Based on this, drug interactions with other CYP3A4 substrates might be expected, however, the clinical relevance is dependent on the pharmacological and pharmacokinetic properties of the substrate involved.”

Statement removed

“No examples of interactions between Livial and other medicines have been reported in clinical practice. However, the following potential interactions should be considered on a theoretical basis: Enzyme inducing compounds such as barbiturates, carbamazepine, hydantoins and rifampicin may enhance the metabolism of tibolone and thus decrease its therapeutic effect”

Section 4.8

Section Updated

Section 5.1

Statement added under prevention of osteoporosis:

“In the LIFT study, tibolone reduced the number of women (mean age 68 years) with new vertebral fractures compared to placebo during the 3 years of treatment (ITT: tibolone to placebo odds ratio 0.57; 95% CI [0.42, 0.78]).”

Section 6.2

Statement changed:

Section 6.5

Section updated

Section 9

Date of renewal updated

Section 10

Date of revision of text updated

Section 4.3 Strikethrough text has been deleted and bold underline text added:

Active or recent Any history of arterial thromboembolic disease (e.g. angina, myocardial infarction, stroke or TIA);

Section 4.4 Strikethrough text has been deleted and bold underline text added:

It is unknown whether the increased risk also extends to other HRT products.

Preliminary results of a randomized double-blind placebo-controlled study (LIFT study, N = 4538) on the efficacy of low dose (1.25mg) tibolone (N = 2267) for the treatment of osteoporosis in elderly women (mean age 68 years), has shown an increased risk of stroke compared to placebo after an average of 2.75 years of follow-up. The incidence of strokes observed in the placebo and tibolone arms was 1.8 and 4.1 per 1000 women-years respectively, a difference of approximately 11.5 extra cases per 1000 women over a 5 year period, corresponding to a relative risk of 2.3 (p=0.02).

Section 4.8 Bold underline text added:

Stroke

The LIFT study has estimated a 2.3-fold increase in the risk of stroke in women (mean age 68 years) who used 1.25mg tibolone compared with placebo (RR 2.3, p=0.02). The absolute risk increase is 2.3 strokes per 1000 women treated per year. See section 4.4.